Linear accelerator-based single-fraction stereotactic radiosurgery versus hypofractionated stereotactic radiotherapy for intact and resected brain metastases up to 3 cm: A multi-institutional retrospective analysis

Introduction: Single-fraction stereotactic radiosurgery (SF-SRS) is typically used to provide local control of brain metastases. Recently, hypofractionated stereotactic radiotherapy (HF-SRT) has been utilized for large brain metastases. Data comparing these two modalities are limited for brain metastases ≤3 cm. Methods: Patients with brain metastases receiving linear accelerator-based SF-SRS or HF-SRT were identified at three institutions. Local progression-free survival (LPFS), intracranial progression-free survival (ICPFS), overall survival (OS), and radionecrosis-free survival (RNFS) were determined from time of treatment. Results: 108 patients (76 intact, 32 resected) with 184 brain metastases (142 intact, 42 resected) were included. There were no significant differences between SF-SRS and HF-SRT for intact metastases in 1-year LPFS (62.8% vs. 58.5%, p=0.631), ICPFS (56.9% vs. 55.3%, p=0.300), and OS (71.6% vs. 70.6%, p=0.096), or for resected metastases in 1-year LPFS (67.3% vs. 57.8%, p=0.288), ICPFS (64.8% vs. 57%, p=0.291), and OS (64.8% vs. 66.1%, p=0.603). There were also no significant differences in 1-year RNFS between SF-SRS and HF-SRT (92% vs. 92%, p=0.325). Conclusions: There were no significant differences in LPFS, ICPFS, OS, and RNFS between SF-SRS and HF-SRT for brain metastases ≤3 cm suggesting SF-SRS may be preferred due to similar outcomes and reduced number of fractions.


INTRODUCTION
Brain metastases are a significant cause of morbidity and mortality for 20% of patients with cancer. 1 For patients with brain metastases, the mainstays of treatment are radiation, surgery, and pharmacotherapy using targeted agents, immunotherapy, and/or chemotherapy. Since the advent of single-fraction stereotactic radiosurgery (SF-SRS), radiation has become increasingly used to provide local control of intracranial metastatic disease. 2 SF-SRS offers advantages over whole brain radiotherapy by limiting neurotoxicity and providing similar long-term survival to both intact and resected brain metastases. [3][4][5] More recently, hypofractionated stereotactic radiotherapy (HF-SRT) has been used for the treatment of brain metastases that are large or high-risk in order to minimize toxicity. 6,7 HF-SRT is similar to SF-SRS in that it is highly conformal stereotactic radiation; however, it is delivered over 2-5 fractions. HF-SRT offers theoretical radiobiological benefits as well as a similar safety and efficacy profile to SF-SRS when used to treat intact brain metastases. 6,8,9 Similarly, other case series have suggested adequate control and improved safety profile of post-operative HF-SRT to resected brain metastases. 5,7,10,11 However, little data exists comparing these treatment modalities for brain metastases up to 3 cm in size. We sought to carry out a multi-institutional retrospective analysis comparing outcomes following linear accelerator-based SF-SRS and HF-SRT for the treatment of brain metastases up to 3 cm, with the unique advantage of stratifying by delivery to intact versus resected tumors.

MATERIALS AND METHODS
This retrospective database study was approved by the institutional review boards of Yale School of Medicine, UConn Health, and Hartford HealthCare. A total of 108 consecutive patients with 184 total brain metastases diagnosed between 2010-19 were included in the study according to the following inclusion and exclusion criteria:

Inclusion Criteria
• Age ≥ 18 with histologically proven solid cancer with brain metastases diagnosed by brain magnetic resonance imaging (MRI) • Patients treated with linear accelerator-based SF-SRS or HF-SRT.
• Brain metastases ≤ 3 cm in diameter • No limit was placed on the number of brain metastases

Exclusion Criteria
• Age < 18 • Absence of follow-up data at least 3 months following treatment • Brain metastases >3 cm in diameter • Patients treated with Gamma Knife (which was available at one institution but not the other two institutions), in order to minimize confounding of results based on technology availability

Target Delineation and Dose comparison
Target delineation, PTV margin expansion, dose prescription, and fractionation were at the discretion of the treating radiation oncologist. The biological effect of radiation treatment among the patients in our cohort was calculated using the biologically effective dose (BED 10 ), which accounts for total dose and dose per fraction. 12 BED 10 was calculated using the linear quadratic equation, with α/β set to 10, d equal to the dose per fraction in Gray units (Gy 10 ), and n equal to the number of fractions delivered.

BED
dn d

Outcomes
Patient outcome data were analyzed retrospectively in a de-identified manner. For intact brain metastases, tumor progression was assessed utilizing the Response Assessment in Neuro-Oncology Brain Metastases criteria defining progression as an increase in tumor diameter > 20% on interval MRIs. 13 For resected brain metastases, progression was determined by the physician based upon clinical and radiographic findings. Local progression-free survival (LPFS) was defined for each metastasis as time from treatment completion to lesion progression of the targeted brain metastasis or death. Intracranial progression-free survival (ICPFS) was defined for each patient as time from treatment completion to any intracranial progression of disease or death. Overall survival (OS) was measured for each patient as time from treatment completion to death. Radionecrosis-free survival (RNFS) was measured for each metastasis as time from treatment completion to clinically apparent radionecrosis either by MRI or pathology following surgical resection. For patients with both intact and resected brain metastases, metastasis-level outcomes (LPFS and RNFS) were calculated for each individual metastasis; however, patient level outcomes (ICPFS and OS) were calculated for each patient based on the first metastasis that was treated.

Statistical Analysis
Patient characteristics were compared using the independent sample t-test for numerical data and chisquare analysis for categorical data. The Kaplan-Meier method was used to compare LPFS, ICPFS, and OS (stratified by intact versus resected metastases) as well as RNFS (intact and resected metastases were combined for analytic purposes due to a small number of events). Data analysis was conducted using SPSS version 22. Statistical significance was two-sided and set at P < 0.05. Cox proportional hazards model was used to adjust for differences in modality, sex, race, histology, location, size, and number of metastases.

Patient Demographics and Tumor Variables
Baseline characteristics for patients receiving radiotherapy to intact and resected brain metastases summarized in Tables 1 and 2 respectively.
In total, 76 patients received radiotherapy to intact brain metastases with SF-SRS (n=45) or HF-SRT (n=31). Among these patients, 142 intact brain metastases were treated with either SF-SRS (n=92) or HF-SRT (n=50). The median dose and interquartile range (IQR) for the SF-SRS group was 21 Gy (20-22 Gy) with a median BED 10  There were no significant differences between the two groups in sex or race. However, statistically significant differences existed in tumor size with a median diameter and IQR of 0.6 cm (0.4-1.0 cm), mean 0.74 cm with 7.6% >1.5 cm in diameter for the SF-SRS group and median diameter and IQR of 1.3 cm (0.9-2.0 cm), mean 1.46 cm with 38% > 1.5 cm for the HF-SRT group (p=0.00001). Additionally, patients with lung cancer (65.2% vs 30.0%; p=0.000026), cerebral cortex metastases (71.7% vs. 54.0%; p=0.04634), or with multiple brain metastases (69.6% vs 46.0%; p=0.0059) were more likely to receive SF-SRS as compared with HF-SRT (Table 1).

Intact Brain Metastases
Local Progression-Free Survival For intact brain metastases treated with SF-SRS or HF-SRT, with a median follow up time of 10 months, the estimated LPFS at 6 months, 12 months, and 18 months were 76.8%, 62.8%, and 46.8% for the SF-SRS group and 67.5%, 58.5%, and 45.3% in the HF-SRT group respectively. There was no statistically significant difference in LPFS between SF-SRS and HF-SRT (P=0.638) ( Figure 1A). Correspondingly on multivariable analysis, HF-SRT was not associated with a change in LPFS (HR 0.932; 95% CI 0.  (Table S1). Lastly, since multiple HF-SRT fractionation regimens were used, we compared LPFS of patients treated with HF-SRT with BED 10 < 45 Gy and BED 10 ≥ 45 Gy and found no significant difference in LPFS (p=0.330) ( Figure S1A).

Intracranial Progression-Free Survival
The Kaplan-Meier plot for ICPFS is shown in Figure 1B. The estimated ICPFS at 6 months, 12 months, and 18 months were 77.3%, 56.9%, and 44.4% for the SF-SRS group and 73.7%, 55.3%, and 49.8% in the HF-SRT group. There was no statistically significant difference in ICPFS between SF-SRS and HF-SRT (P=0.300). Correspondingly, on multivariable analysis HF-SRT was not associated with ICPFS (HR 0.817; 95% CI 0.311-2.147; p=0.681). There were no independent predictors of increased risk of intracranial progression on multivariable analyses (Table S1).

Overall Survival
The Kaplan-Meier plot for OS is shown in Figure 1C. The estimated OS at 6 months, 12 months, and 18 months The only predictor of worse survival on multivariable analysis was other histology (non-breast, melanoma, or lung) conferring a higher risk of death (HR 6.709; 95% CI 1.516-29.696; p=0.012) (Table S1).

Radionecrosis-Free Survival
There was a very low rate of radionecrosis in our entire study cohort. Specifically, the low overall number of events in the resected group precluded further statistical analysis. Therefore, in the next section combined RNFS data for both intact and resected are reported.

Resected Brain Metastases Local Progression-Free Survival
For resected brain metastases, with a median follow up time of 11 months, the estimated ICPFS at 6 months, 12 months, and 18 months were 76.9%, 67.3%, and 50.5% for the SF-SRS group and 81.3%, 57.8%, and 44.5% for the HF-SRT. There was no statistically significant difference between SF-SRS and HF-SRT as measured by LPFS (P=0.288) (Figure 2A). Correspondingly, HF-SRT was not associated with worse LPFS (HR 1.486; 95% CI 0.484-4.564; p=0.489). There were no significant predictors of LPFS identified on multivariable analyses (Table S2). Lastly, since multiple HF-SRT fractionation regimens were used, we compared LPFS of patients treated with HF-SRT with BED 10 < 45 Gy and BED 10 ≥ 45 Gy and found no significant difference in LPFS (p=0.462) ( Figure S1B).

Intracranial Progression-Free Survival
The Kaplan-Meier plot for ICPFS is shown in Figure 2B. The estimated ICPFS at 6 months, 12 months, and 18 months were 77.8%, 64.8%, and 48.6% for the SF-SRS group and 77%, 57.4%, and 40.1% for the HF-SRT group. There was no statistically significant difference in ICPFS between the SF-SRS and HF-SRT groups (P=0.291). Likewise, on multivariable analysis HF-SRT was not associated with an ICPFS (HR 1.825; 0.523-6.367; p=0.345). There were no significant predictors of ICPFS identified on multivariable analyses (Table S2).

Overall Survival
The Kaplan-Meier plot for OS is shown in Figure 2C. The estimated OS at 6 months, 12 months, and 18 months were 77.8%, 64.8%, and 48.6% for the SF-SRS group and 81.3%, 66.1%, and 47.3% for the HF-SRT group. There was no statistically significant difference in OS between the SF-SRS and HF-SRT groups (P=0.603). Similarly, HF-SRT was not associated with a difference in risk of death (HR 0.843; 95% CI 0.203-3.494; p=0.814). There were no significant predictors of OS identified on multivariable analyses (Table S2). were 84.1%, 71.1% and 55.8% for the SF-SRS group and 89.6%, 70.6%, and 65.1% for the HF-SRT group. There was no statistically significant difference in OS between SF-SRS and HF-SRT (P=0.096). On multivariable analysis there was also no difference in risk of death for HF-SRT (HR 0.557; 95% CI 0.199-1.557; p=0.264).

Radionecrosis-Free Survival
The Kaplan-Meier plot for RNFS for both intact and resected brain metastases combined is shown in Figure 3. These data were combined for analysis due to the low event rate and in particular the low over-all number of events in the resected group which precluded further statistical analysis. The estimated RNFS at 6 months, 12 months, and 18 months were 97.8%, 92.0%, and 92.0% for the SF-SRS group and 98.7%, 92.0%, and 92.0% for the HF-SRT group. There was no statistically significant difference in RNFS between SF-SRS and HF-SRT (P=0.325). HF-SRT was not associated with RNFS (HR 1.233; 95% CI 0.270-5.634; p=0.787). There were no significant predictors of RNFS identified on multivariable analyses (Table S3).

DISCUSSION
We found no statistically significant differences between linear accelerator-based SF-SRS and HF-SRT in the control of brain metastases as measured by LPFS, ICPFS, OS, and RNFS for brain metastases up to 3 cm in size. Our observations are consistent with previous studies demonstrating similar clinical outcomes in both LPFS and OS between SF-SRS and HF-SRT both to intact and resected brain metastases. [14][15][16] Our investigation is unique in being the first multi-institutional study exclusively focusing on linear accelerator-based radiosurgical treatments for smaller brain metastases stratified into intact versus resected cohorts.
In a previous case series, the OS at 1 year for intact brain metastases treated with SF-SRS and HF-SRT were not statistically different at 53.1% and 69.4%, respectively. A more recent large multi-institutional case series showed similar local control rates of 90% and 81% for SF-SRS and HF-SRT. 16 Interestingly, a recent meta-analysis of 24 studies analyzing local control of brain metastases larger than 3 cm found a  local control rate of 77.6% for SF-SRS and 92.9% for HF-SRT at one year, suggesting an advantage for HF-SRT; however, single-arm studies were included in this analysis, potentially biasing the conclusions. 17 For resected brain metastases, a recent meta-analysis suggested excellent local control rates of 84%, with a slight benefit to HF-SRT vs. SF-SRS 87% vs. 80%. 18 Additionally, a large single-institutional analysis of post-operative SRS in over 500 patients showed 93% local control at 12 months and 63% intracranial control at 12 months. 19 Similarly, a recent multi-institutional cohort study of 558 patients with resected brain metastases treated with HFRT found a high rate of local control of 84% at one year with low rates of radionecrosis of 8.6%. 20 Our study adds to these findings, suggesting similar local control and overall survival rates for SF-SRS and HF-SRT for both intact and resected brain metastases up to 3 cm in size while offering the advantage of comparing these treatment arms directly at multiple institutions using linear accelerator-only treatment.
Prior studies have suggested lower rates of radionecrosis in HF-SRT; however, these studies focused on patients with larger brain metastases. 6,11,15 In our study focusing on brain metastases up to 3 cm in size, we found similar low rates of radionecrosis between the SF-SRS and HF-SRT. Given the overall low rate of radionecrosis among brain metastasis up to 3 cm, this suggests that the reduction in risk of radionecrosis previously seen may be more notable for larger brain metastases, which have a higher baseline risk of this toxicity.
This study is limited by the differences in patient baseline characteristics discussed above, particularly the differences in tumor size between SF-SRS and HF-SRT in the intact brain metastasis cohort (though this was accounted for in the multivariable analysis). Additionally, non-standardized dose-fractionation schemes and treatment planning across institutions existed in our dataset. At the one institution with Gamma Knife, linear accelerator-based treatment was typically used for HF-SRT, since SF-SRS was usually performed with the Gamma Knife instead. We chose not to include Gamma Knife patients, however, since (1) it was only available at one of the three institutions; and (2) we aimed to minimize the risk of confounding given prior suggestions that Gamma Knife may be associated with differential outcomes compared to linear-accelerator-based radiosurgery. 21 We also did not have detailed patient toxicity outcomes to compare SF-SRS and HF-SRT and were unable to analyze leptomeningeal disease as a specific patient outcome. Lastly, our data set is limited to radiotherapy to intact and resected metastases and did not include any patients with pre-oper-ative radiotherapy, which has been suggested as a potential means to lower rates of radionecrosis and leptomeningeal disease compared to post-operative radiotherapy. 22

CONCLUSIONS
In this retrospective, multi-institutional analysis we found a similar efficacy profile of linear accelerator-based SF-SRS and HF-SRT for the management of both intact and resected brain metastases up to 3 cm. This suggests that SF-SRS may be preferred for tumors ≤3 cm due to a similar safety and efficacy profile and reduced number of fractions. Further prospective studies are warranted to confirm these results.
Supplementary information to this paper can be accessed from the electronic version.